ID FOXP3_MOUSE Reviewed; 429 AA. AC Q99JB6; DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 27-MAR-2024, entry version 187. DE RecName: Full=Forkhead box protein P3; DE AltName: Full=Scurfin; DE Contains: DE RecName: Full=Forkhead box protein P3, C-terminally processed; DE Contains: DE RecName: Full=Forkhead box protein P3 41 kDa form; GN Name=Foxp3; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=11138001; DOI=10.1038/83784; RA Brunkow M.E., Jeffery E.W., Hjerrild K.A., Paeper B., Clark L.B., RA Yasayko S.-A., Wilkinson J.E., Galas D., Ziegler S.F., Ramsdell F.; RT "Disruption of a new forkhead/winged-helix protein, scurfin, results in the RT fatal lymphoproliferative disorder of the scurfy mouse."; RL Nat. Genet. 27:68-73(2001). RN [2] RP FUNCTION. RX PubMed=15790681; DOI=10.1073/pnas.0501675102; RA Bettelli E., Dastrange M., Oukka M.; RT "Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to RT repress cytokine gene expression and effector functions of T helper RT cells."; RL Proc. Natl. Acad. Sci. U.S.A. 102:5138-5143(2005). RN [3] RP HOMODIMERIZATION, AND MUTAGENESIS OF GLU-250. RX PubMed=16769892; DOI=10.1073/pnas.0600225103; RA Chae W.J., Henegariu O., Lee S.K., Bothwell A.L.; RT "The mutant leucine-zipper domain impairs both dimerization and suppressive RT function of Foxp3 in T cells."; RL Proc. Natl. Acad. Sci. U.S.A. 103:9631-9636(2006). RN [4] RP FUNCTION, INTERACTION WITH RUNX1; RUNX2; RUNX3 AND NFATC2, SUBCELLULAR RP LOCATION, AND MUTAGENESIS OF 329-ASP-TYR-330 AND LYS-332. RX PubMed=17377532; DOI=10.1038/nature05673; RA Ono M., Yaguchi H., Ohkura N., Kitabayashi I., Nagamura Y., Nomura T., RA Miyachi Y., Tsukada T., Sakaguchi S.; RT "Foxp3 controls regulatory T-cell function by interacting with RT AML1/Runx1."; RL Nature 446:685-689(2007). RN [5] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RORC, AND INDUCTION. RX PubMed=18368049; DOI=10.1038/nature06878; RA Zhou L., Lopes J.E., Chong M.M., Ivanov I.I., Min R., Victora G.D., RA Shen Y., Du J., Rubtsov Y.P., Rudensky A.Y., Ziegler S.F., Littman D.R.; RT "TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by RT antagonizing RORgammat function."; RL Nature 453:236-240(2008). RN [6] RP PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 48-ARG--ARG-51 AND 414-ARG--ARG-417. RX PubMed=19117830; DOI=10.1074/jbc.m807322200; RA de Zoeten E.F., Lee I., Wang L., Chen C., Ge G., Wells A.D., Hancock W.W., RA Ozkaynak E.; RT "Foxp3 processing by proprotein convertases and control of regulatory T RT cell function."; RL J. Biol. Chem. 284:5709-5716(2009). RN [7] RP FUNCTION, AND INTERACTION WITH IKZF4; HDAC7 AND KAT5. RX PubMed=19696312; DOI=10.1126/science.1176077; RA Pan F., Yu H., Dang E.V., Barbi J., Pan X., Grosso J.F., Jinasena D., RA Sharma S.M., McCadden E.M., Getnet D., Drake C.G., Liu J.O., RA Ostrowski M.C., Pardoll D.M.; RT "Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells."; RL Science 325:1142-1146(2009). RN [8] RP ACETYLATION AT LYS-31; LYS-262 AND LYS-267, AND DEACETYLATION BY SIRT1. RX PubMed=22312127; DOI=10.4049/jimmunol.1100903; RA Kwon H.S., Lim H.W., Wu J., Schnolzer M., Verdin E., Ott M.; RT "Three novel acetylation sites in the Foxp3 transcription factor regulate RT the suppressive activity of regulatory T cells."; RL J. Immunol. 188:2712-2721(2012). RN [9] RP UBIQUITINATION AT LYS-249; LYS-251; LYS-262; LYS-267 AND LYS-393, AND RP DEUBIQUITINATION. RX PubMed=23973222; DOI=10.1016/j.immuni.2013.05.018; RA van Loosdregt J., Fleskens V., Fu J., Brenkman A.B., Bekker C.P., RA Pals C.E., Meerding J., Berkers C.R., Barbi J., Grone A., Sijts A.J., RA Maurice M.M., Kalkhoven E., Prakken B.J., Ovaa H., Pan F., Zaiss D.M., RA Coffer P.J.; RT "Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 RT increases Treg-cell-suppressive capacity."; RL Immunity 39:259-271(2013). RN [10] RP UBIQUITINATION, INTERACTION WITH STUB1 AND HSPA1A/B, AND INDUCTION. RX PubMed=23973223; DOI=10.1016/j.immuni.2013.08.006; RA Chen Z., Barbi J., Bu S., Yang H.Y., Li Z., Gao Y., Jinasena D., Fu J., RA Lin F., Chen C., Zhang J., Yu N., Li X., Shan Z., Nie J., Gao Z., Tian H., RA Li Y., Yao Z., Zheng Y., Park B.V., Pan Z., Zhang J., Dang E., Li Z., RA Wang H., Luo W., Li L., Semenza G.L., Zheng S.G., Loser K., Tsun A., RA Greene M.I., Pardoll D.M., Pan F., Li B.; RT "The ubiquitin ligase Stub1 negatively modulates regulatory T cell RT suppressive activity by promoting degradation of the transcription factor RT Foxp3."; RL Immunity 39:272-285(2013). RN [11] RP PHOSPHORYLATION AT SER-19 AND THR-175, AND MUTAGENESIS OF SER-19; SER-88; RP THR-114 AND THR-175. RX PubMed=23853094; DOI=10.1074/jbc.m113.467704; RA Morawski P.A., Mehra P., Chen C., Bhatti T., Wells A.D.; RT "Foxp3 protein stability is regulated by cyclin-dependent kinase 2."; RL J. Biol. Chem. 288:24494-24502(2013). RN [12] RP REVIEW. RX PubMed=24722479; DOI=10.1038/nri3650; RA Ramsdell F., Ziegler S.F.; RT "FOXP3 and scurfy: how it all began."; RL Nat. Rev. Immunol. 14:343-349(2014). RN [13] {ECO:0007744|PDB:4I1L} RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 189-276, SUBUNIT, AND FUNCTION. RX PubMed=22813742; DOI=10.1016/j.celrep.2012.04.012; RA Song X., Li B., Xiao Y., Chen C., Wang Q., Liu Y., Berezov A., Xu C., RA Gao Y., Li Z., Wu S.L., Cai Z., Zhang H., Karger B.L., Hancock W.W., RA Wells A.D., Zhou Z., Greene M.I.; RT "Structural and biological features of FOXP3 dimerization relevant to RT regulatory T cell function."; RL Cell Rep. 1:665-675(2012). CC -!- FUNCTION: Transcriptional regulator which is crucial for the CC development and inhibitory function of regulatory T-cells (Treg) CC (PubMed:22813742). Plays an essential role in maintaining homeostasis CC of the immune system by allowing the acquisition of full suppressive CC function and stability of the Treg lineage, and by directly modulating CC the expansion and function of conventional T-cells. Can act either as a CC transcriptional repressor or a transcriptional activator depending on CC its interactions with other transcription factors, histone acetylases CC and deacetylases. The suppressive activity of Treg involves the CC coordinate activation of many genes, including CTLA4 and TNFRSF18 by CC FOXP3 along with repression of genes encoding cytokines such as CC interleukin-2 (IL2) and interferon-gamma (IFNG). Inhibits cytokine CC production and T-cell effector function by repressing the activity of CC two key transcription factors, RELA and NFATC2 (PubMed:15790681). CC Mediates transcriptional repression of IL2 via its association with CC histone acetylase KAT5 and histone deacetylase HDAC7 (By similarity). CC Can activate the expression of TNFRSF18, IL2RA and CTLA4 and repress CC the expression of IL2 and IFNG via its association with transcription CC factor RUNX1 (PubMed:17377532). Inhibits the differentiation of IL17 CC producing helper T-cells (Th17) by antagonizing RORC function, leading CC to down-regulation of IL17 expression, favoring Treg development CC (PubMed:18368049). Inhibits the transcriptional activator activity of CC RORA (By similarity). Can repress the expression of IL2 and IFNG via CC its association with transcription factor IKZF4 (PubMed:19696312). CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:15790681, CC ECO:0000269|PubMed:17377532, ECO:0000269|PubMed:18368049, CC ECO:0000269|PubMed:19696312, ECO:0000269|PubMed:22813742}. CC -!- SUBUNIT: Homodimer (PubMed:22813742). Dimerization is essential for its CC transcriptional regulator activity. Interacts with IKZF3 (By CC similarity). Interacts (via LXXLL motif) with isoform 4 of RORA (via CC AF-2 motif) (By similarity). Interacts with STUB1 and HSPA1A/B. CC Interacts with IKZF4, HDAC7 and KAT5. Interacts with RUNX1, RUNX2, CC RUNX3 and NFATC2. Interacts with RORC. Interacts with HDAC9 in the CC absence of T-cell stimulation (By similarity). Interacts with RELA, CC PPP1CA, PPP1CB, PPP1CG, HSPA8 and USP7 (By similarity). CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:16769892, CC ECO:0000269|PubMed:17377532, ECO:0000269|PubMed:18368049, CC ECO:0000269|PubMed:19696312, ECO:0000269|PubMed:22813742, CC ECO:0000269|PubMed:23973223}. CC -!- INTERACTION: CC Q99JB6; Q03347: Runx1; NbExp=5; IntAct=EBI-10956246, EBI-3863873; CC Q99JB6; Q8C2S0: Usp44; NbExp=3; IntAct=EBI-10956246, EBI-26303241; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00089, CC ECO:0000269|PubMed:17377532, ECO:0000269|PubMed:18368049}. Cytoplasm CC {ECO:0000250|UniProtKB:Q9BZS1}. Note=Predominantly expressed in the CC cytoplasm in activated conventional T-cells whereas predominantly CC expressed in the nucleus in regulatory T-cells (Treg) (By similarity). CC The 41 kDa form derived by proteolytic processing is found exclusively CC in the chromatin fraction of activated Treg cells. CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:19117830}. CC -!- TISSUE SPECIFICITY: High level of expression in thymus and spleen. CC -!- INDUCTION: By TGFB1 in T-cells. Down-regulated in regulatory T-cells CC (Treg) during inflammation. {ECO:0000269|PubMed:18368049, CC ECO:0000269|PubMed:23973223}. CC -!- DOMAIN: The fork-head DNA-binding domain is essential for its CC dimerization and interaction with NFATC2. CC {ECO:0000250|UniProtKB:Q9BZS1}. CC -!- PTM: Acetylation on lysine residues stabilizes FOXP3 and promotes CC differentiation of T-cells into induced regulatory T-cells (iTregs) CC associated with suppressive functions (PubMed:22312127). Acetylation is CC mediated by a coordinated action of KAT5 and EP300/p300 CC acetyltransferases: EP300/p300 is required to enhance KAT5 CC autoacetylation, promoting acetylation of FOXP3 by KAT5 (By CC similarity). Deacetylated by SIRT1 (PubMed:22312127). CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:22312127}. CC -!- PTM: Polyubiquitinated, leading to its proteasomal degradation in CC regulatory T-cells (Treg) which is mediated by STUB1 in a HSPA1A/B- CC dependent manner. Deubiquitinated by USP7 and USP44 leading to increase CC in protein stability. {ECO:0000269|PubMed:23973222, CC ECO:0000269|PubMed:23973223}. CC -!- PTM: Phosphorylation at Ser-418 regulates its transcriptional repressor CC activity and consequently, regulatory T-cells (Treg) suppressive CC function (By similarity). Phosphorylation by CDK2 negatively regulates CC its transcriptional activity and protein stability. CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:23853094}. CC -!- PTM: Undergoes proteolytic cleavage in activated regulatory T-cells CC (Treg), and can be cleaved at either the N- or C-terminal site, or at CC both sites. Treg expressing the form cleaved at C-terminal site or both CC N- and C-terminal sites exhibit an increased induction of IL10 and an CC increased capacity to suppress proliferation of conventional T-cells in CC vitro. Treg expressing the form cleaved at only the C-terminal site are CC highly effective at preventing experimental colitis in an in vivo model CC of inflammatory bowel disease. {ECO:0000269|PubMed:19117830}. CC -!- DISEASE: Note=Defects in Foxp3 are the cause of the scurfy phenotype CC (sf). It results in a lethal disorder of immunoregulation, CC characterized by infections, diarrhea, anemia, thrombocytopenia, CC hypogonadism, gastrointestinal bleeding, lymphadenopathy and CC leukocytosis. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF277994; AAG53608.1; -; Genomic_DNA. DR EMBL; AF277991; AAG53605.1; -; mRNA. DR EMBL; AF277992; AAG53606.1; -; mRNA. DR CCDS; CCDS29965.1; -. DR RefSeq; NP_001186276.1; NM_001199347.1. DR RefSeq; NP_001186277.1; NM_001199348.1. DR RefSeq; NP_473380.1; NM_054039.2. DR PDB; 4I1L; X-ray; 2.10 A; A=189-276. DR PDB; 7TDW; X-ray; 4.00 A; A=204-417. DR PDB; 7TDX; X-ray; 3.10 A; A=204-417. DR PDB; 8SRO; EM; 3.30 A; A/B/C/D=188-423. DR PDB; 8SRP; EM; 3.70 A; A/B/C/D/E/F/G/H/I/J=188-423. DR PDBsum; 4I1L; -. DR PDBsum; 7TDW; -. DR PDBsum; 7TDX; -. DR PDBsum; 8SRO; -. DR PDBsum; 8SRP; -. DR AlphaFoldDB; Q99JB6; -. DR EMDB; EMD-40736; -. DR EMDB; EMD-40737; -. DR SMR; Q99JB6; -. DR BioGRID; 203183; 371. DR DIP; DIP-59739N; -. DR IntAct; Q99JB6; 14. DR MINT; Q99JB6; -. DR STRING; 10090.ENSMUSP00000111405; -. DR GlyGen; Q99JB6; 10 sites, 1 O-linked glycan (10 sites). DR iPTMnet; Q99JB6; -. DR PhosphoSitePlus; Q99JB6; -. DR PaxDb; 10090-ENSMUSP00000111405; -. DR ProteomicsDB; 267500; -. DR Antibodypedia; 485; 2249 antibodies from 53 providers. DR DNASU; 20371; -. DR Ensembl; ENSMUST00000045566.7; ENSMUSP00000041953.7; ENSMUSG00000039521.14. DR Ensembl; ENSMUST00000115738.8; ENSMUSP00000111403.2; ENSMUSG00000039521.14. DR Ensembl; ENSMUST00000115739.9; ENSMUSP00000111404.2; ENSMUSG00000039521.14. DR Ensembl; ENSMUST00000115740.9; ENSMUSP00000111405.2; ENSMUSG00000039521.14. DR Ensembl; ENSMUST00000234363.2; ENSMUSP00000157093.2; ENSMUSG00000039521.14. DR Ensembl; ENSMUST00000235116.2; ENSMUSP00000157059.2; ENSMUSG00000039521.14. DR GeneID; 20371; -. DR KEGG; mmu:20371; -. DR UCSC; uc009sll.2; mouse. DR AGR; MGI:1891436; -. DR CTD; 50943; -. DR MGI; MGI:1891436; Foxp3. DR VEuPathDB; HostDB:ENSMUSG00000039521; -. DR eggNOG; KOG4385; Eukaryota. DR GeneTree; ENSGT00940000161807; -. DR HOGENOM; CLU_019502_1_0_1; -. DR InParanoid; Q99JB6; -. DR OMA; HCQVDHL; -. DR OrthoDB; 5385885at2759; -. DR PhylomeDB; Q99JB6; -. DR TreeFam; TF326978; -. DR Reactome; R-MMU-8877330; RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs). DR BioGRID-ORCS; 20371; 5 hits in 122 CRISPR screens. DR PRO; PR:Q99JB6; -. DR Proteomes; UP000000589; Chromosome X. DR RNAct; Q99JB6; Protein. DR Bgee; ENSMUSG00000039521; Expressed in urethra and 52 other cell types or tissues. DR ExpressionAtlas; Q99JB6; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; ISO:MGI. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:MGI. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:MGI. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IBA:GO_Central. DR GO; GO:0035035; F:histone acetyltransferase binding; ISO:MGI. DR GO; GO:0042826; F:histone deacetylase binding; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; IPI:MGI. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0051525; F:NFAT protein binding; ISS:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI. DR GO; GO:0003714; F:transcription corepressor activity; IDA:MGI. DR GO; GO:0046633; P:alpha-beta T cell proliferation; IMP:MGI. DR GO; GO:0001782; P:B cell homeostasis; IMP:MGI. DR GO; GO:0043367; P:CD4-positive, alpha-beta T cell differentiation; IDA:MGI. DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IDA:MGI. DR GO; GO:0002361; P:CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation; IMP:MGI. DR GO; GO:0002362; P:CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment; TAS:UniProtKB. DR GO; GO:0006338; P:chromatin remodeling; IDA:MGI. DR GO; GO:0006351; P:DNA-templated transcription; IDA:MGI. DR GO; GO:0014045; P:establishment of endothelial blood-brain barrier; IEA:Ensembl. DR GO; GO:0010467; P:gene expression; IMP:MGI. DR GO; GO:0033080; P:immature T cell proliferation in thymus; IMP:MGI. DR GO; GO:0006954; P:inflammatory response; IMP:MGI. DR GO; GO:0048289; P:isotype switching to IgE isotypes; IMP:MGI. DR GO; GO:0046651; P:lymphocyte proliferation; IMP:MGI. DR GO; GO:0002262; P:myeloid cell homeostasis; IMP:MGI. DR GO; GO:0046642; P:negative regulation of alpha-beta T cell proliferation; IMP:MGI. DR GO; GO:2000562; P:negative regulation of CD4-positive, alpha-beta T cell proliferation; IDA:MGI. DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:0002677; P:negative regulation of chronic inflammatory response; IDA:MGI. DR GO; GO:0032792; P:negative regulation of CREB transcription factor activity; ISS:UniProtKB. DR GO; GO:0001818; P:negative regulation of cytokine production; ISS:UniProtKB. DR GO; GO:0050687; P:negative regulation of defense response to virus; ISO:MGI. DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISS:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:MGI. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:MGI. DR GO; GO:0050777; P:negative regulation of immune response; ISS:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:MGI. DR GO; GO:0032693; P:negative regulation of interleukin-10 production; IMP:MGI. DR GO; GO:0032700; P:negative regulation of interleukin-17 production; IMP:UniProtKB. DR GO; GO:0032703; P:negative regulation of interleukin-2 production; IDA:UniProtKB. DR GO; GO:0032713; P:negative regulation of interleukin-4 production; IDA:MGI. DR GO; GO:0032714; P:negative regulation of interleukin-5 production; IDA:MGI. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IMP:MGI. DR GO; GO:0048294; P:negative regulation of isotype switching to IgE isotypes; IMP:MGI. DR GO; GO:0050672; P:negative regulation of lymphocyte proliferation; IMP:MGI. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:UniProtKB. DR GO; GO:0002725; P:negative regulation of T cell cytokine production; ISS:UniProtKB. DR GO; GO:0042130; P:negative regulation of T cell proliferation; IDA:MGI. DR GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; ISS:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:MGI. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IMP:MGI. DR GO; GO:0032689; P:negative regulation of type II interferon production; IDA:UniProtKB. DR GO; GO:0043372; P:positive regulation of CD4-positive, alpha-beta T cell differentiation; IDA:MGI. DR GO; GO:0032831; P:positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation; IMP:MGI. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:MGI. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:MGI. DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; IMP:MGI. DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IMP:MGI. DR GO; GO:0002851; P:positive regulation of peripheral T cell tolerance induction; IMP:MGI. DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; IDA:MGI. DR GO; GO:0002669; P:positive regulation of T cell anergy; IMP:MGI. DR GO; GO:0002666; P:positive regulation of T cell tolerance induction; IMP:MGI. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI. DR GO; GO:0032914; P:positive regulation of transforming growth factor beta1 production; IDA:MGI. DR GO; GO:0002637; P:regulation of immunoglobulin production; IMP:MGI. DR GO; GO:0048302; P:regulation of isotype switching to IgG isotypes; IMP:MGI. DR GO; GO:0002667; P:regulation of T cell anergy; IMP:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IGI:MGI. DR GO; GO:0045066; P:regulatory T cell differentiation; IDA:MGI. DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:1901355; P:response to rapamycin; IEA:Ensembl. DR GO; GO:0009615; P:response to virus; IEA:Ensembl. DR GO; GO:0042110; P:T cell activation; IMP:MGI. DR GO; GO:0002870; P:T cell anergy; IMP:MGI. DR GO; GO:0002456; P:T cell mediated immunity; IMP:MGI. DR GO; GO:0042098; P:T cell proliferation; IDA:MGI. DR GO; GO:0050852; P:T cell receptor signaling pathway; IMP:MGI. DR GO; GO:0002517; P:T cell tolerance induction; IMP:MGI. DR GO; GO:0002507; P:tolerance induction; IDA:MGI. DR GO; GO:0002513; P:tolerance induction to self antigen; IMP:MGI. DR GO; GO:0006366; P:transcription by RNA polymerase II; IDA:MGI. DR GO; GO:0032905; P:transforming growth factor beta1 production; IDA:MGI. DR CDD; cd20066; FH_FOXP3; 1. DR Gene3D; 1.20.5.340; -; 1. DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1. DR InterPro; IPR047413; FH_FOXP3. DR InterPro; IPR001766; Fork_head_dom. DR InterPro; IPR032354; FOXP-CC. DR InterPro; IPR030456; TF_fork_head_CS_2. DR InterPro; IPR036388; WH-like_DNA-bd_sf. DR InterPro; IPR036390; WH_DNA-bd_sf. DR InterPro; IPR013087; Znf_C2H2_type. DR PANTHER; PTHR45796; FORKHEAD BOX P, ISOFORM C; 1. DR PANTHER; PTHR45796:SF5; FORKHEAD BOX PROTEIN P3; 1. DR Pfam; PF00250; Forkhead; 1. DR Pfam; PF16159; FOXP-CC; 1. DR PRINTS; PR00053; FORKHEAD. DR SMART; SM00339; FH; 1. DR SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1. DR PROSITE; PS00658; FORK_HEAD_2; 1. DR PROSITE; PS50039; FORK_HEAD_3; 1. DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1. DR Genevisible; Q99JB6; MM. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Activator; Cytoplasm; DNA-binding; KW Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; KW Reference proteome; Repressor; Transcription; Transcription regulation; KW Ubl conjugation; Zinc; Zinc-finger. FT CHAIN 1..429 FT /note="Forkhead box protein P3" FT /id="PRO_0000091888" FT CHAIN 1..417 FT /note="Forkhead box protein P3, C-terminally processed" FT /evidence="ECO:0000305|PubMed:19117830" FT /id="PRO_0000432436" FT CHAIN 52..417 FT /note="Forkhead box protein P3 41 kDa form" FT /evidence="ECO:0000305|PubMed:19117830" FT /id="PRO_0000432437" FT PROPEP 418..429 FT /evidence="ECO:0000305|PubMed:19117830" FT /id="PRO_0000432438" FT ZN_FING 196..221 FT /note="C2H2-type" FT DNA_BIND 337..423 FT /note="Fork-head" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089" FT REGION 1..67 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 105..189 FT /note="Essential for transcriptional repressor activity and FT for interaction with KAT5 and HDAC7" FT /evidence="ECO:0000250|UniProtKB:Q9BZS1" FT REGION 148..198 FT /note="Interaction with IKZF4" FT /evidence="ECO:0000269|PubMed:19696312" FT REGION 238..259 FT /note="Leucine-zipper" FT REGION 277..336 FT /note="Interaction with RUNX1" FT /evidence="ECO:0000250|UniProtKB:Q9BZS1" FT MOTIF 67..75 FT /note="Nuclear export signal" FT /evidence="ECO:0000250|UniProtKB:Q9BZS1" FT MOTIF 91..95 FT /note="LXXLL motif" FT /evidence="ECO:0000250|UniProtKB:Q9BZS1" FT MOTIF 238..247 FT /note="Nuclear export signal" FT /evidence="ECO:0000250|UniProtKB:Q9BZS1" FT MOTIF 414..417 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250|UniProtKB:Q9BZS1" FT COMPBIAS 51..66 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 51..52 FT /note="Cleavage" FT /evidence="ECO:0000269|PubMed:19117830" FT SITE 417..418 FT /note="Cleavage; by PCSK1 or PCSK2" FT /evidence="ECO:0000269|PubMed:19117830" FT MOD_RES 19 FT /note="Phosphoserine; by CDK2" FT /evidence="ECO:0000269|PubMed:23853094" FT MOD_RES 31 FT /note="N6-acetyllysine" FT /evidence="ECO:0000269|PubMed:22312127" FT MOD_RES 175 FT /note="Phosphothreonine; by CDK2" FT /evidence="ECO:0000269|PubMed:23853094" FT MOD_RES 262 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:22312127" FT MOD_RES 267 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000269|PubMed:22312127" FT MOD_RES 418 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9BZS1" FT CROSSLNK 249 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23973222" FT CROSSLNK 251 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23973222" FT CROSSLNK 262 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:23973222" FT CROSSLNK 267 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:23973222" FT CROSSLNK 393 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23973222" FT MUTAGEN 19 FT /note="S->A: Loss of phosphorylation. Increase in protein FT stability, transcriptional activity and the ability to FT suppress the proliferation of conventional T-cells in FT vitro; when associated with A-88; A-114 and A-175." FT /evidence="ECO:0000269|PubMed:23853094" FT MUTAGEN 48..51 FT /note="RDLR->HDLH: Loss of proteolytic processing." FT /evidence="ECO:0000269|PubMed:19117830" FT MUTAGEN 88 FT /note="S->A: Increase in protein stability, transcriptional FT activity and the ability to suppress the proliferation of FT conventional T-cells in vitro; when associated with A-19; FT A-114 and A-175." FT /evidence="ECO:0000269|PubMed:23853094" FT MUTAGEN 114 FT /note="T->A: Increase in protein stability, transcriptional FT activity and the ability to suppress the proliferation of FT conventional T-cells in vitro; when associated with A-19; FT A-88 and A-175." FT /evidence="ECO:0000269|PubMed:23853094" FT MUTAGEN 175 FT /note="T->A: Increase in protein stability, transcriptional FT activity and the ability to suppress the proliferation of FT conventional T-cells in vitro; when associated with A-19; FT A-88 and A-114." FT /evidence="ECO:0000269|PubMed:23853094" FT MUTAGEN 250 FT /note="Missing: Loss of homodimerization, decrease in FT transcriptional repressor activity, elimination of its Treg FT suppressor activity, defects in Th1 and Th2 cytokine FT secretion and down-regulation of cell surface markers on FT regulatory T-cells." FT /evidence="ECO:0000269|PubMed:16769892" FT MUTAGEN 329..330 FT /note="DY->VH: Reduced interaction with RUNX1, decrease in FT its ability to regulate the expression of IL2, TNFRSF18, FT IL2RA and CTLA4 in a RUNX1-dependent manner. Loss of FT interaction with RUNX1 but no effect on interaction with FT NFATC2 and loss of its ability to regulate the expression FT of IL2, TNFRSF18, IL2RA and CTLA4 in a RUNX1-dependent FT manner; when associated with L-332." FT /evidence="ECO:0000269|PubMed:17377532" FT MUTAGEN 332 FT /note="K->L: Loss of interaction with RUNX1 but no effect FT on interaction with NFATC2 and loss of its ability to FT regulate the expression of IL2, TNFRSF18, IL2RA and CTLA4 FT in a RUNX1-dependent manner; when associated with FT 329-VH-330." FT /evidence="ECO:0000269|PubMed:17377532" FT MUTAGEN 414..417 FT /note="RKKR->PNNW: Loss of ability to suppress the FT proliferation of effector T-cells." FT /evidence="ECO:0000269|PubMed:19117830" FT MUTAGEN 414..417 FT /note="RKKR->QNKS: Loss of proteolytic processing." FT /evidence="ECO:0000269|PubMed:19117830" FT TURN 204..207 FT /evidence="ECO:0007829|PDB:4I1L" FT HELIX 208..257 FT /evidence="ECO:0007829|PDB:4I1L" FT HELIX 342..352 FT /evidence="ECO:0007829|PDB:7TDX" FT HELIX 360..370 FT /evidence="ECO:0007829|PDB:7TDX" FT HELIX 373..375 FT /evidence="ECO:0007829|PDB:7TDX" FT HELIX 378..391 FT /evidence="ECO:0007829|PDB:7TDX" FT STRAND 395..399 FT /evidence="ECO:0007829|PDB:7TDX" FT STRAND 401..408 FT /evidence="ECO:0007829|PDB:7TDX" SQ SEQUENCE 429 AA; 47346 MW; 28D5B8E67891840C CRC64; MPNPRPAKPM APSLALGPSP GVLPSWKTAP KGSELLGTRG SGGPFQGRDL RSGAHTSSSL NPLPPSQLQL PTVPLVMVAP SGARLGPSPH LQALLQDRPH FMHQLSTVDA HAQTPVLQVR PLDNPAMISL PPPSAATGVF SLKARPGLPP GINVASLEWV SREPALLCTF PRSGTPRKDS NLLAAPQGSY PLLANGVCKW PGCEKVFEEP EEFLKHCQAD HLLDEKGKAQ CLLQREVVQS LEQQLELEKE KLGAMQAHLA GKMALAKAPS VASMDKSSCC IVATSTQGSV LPAWSAPREA PDGGLFAVRR HLWGSHGNSS FPEFFHNMDY FKYHNMRPPF TYATLIRWAI LEAPERQRTL NEIYHWFTRM FAYFRNHPAT WKNAIRHNLS LHKCFVRVES EKGAVWTVDE FEFRKKRSQR PNKCSNPCP //